KRAS mutation is enormous problem in oncology and results in hundreds of thousands of deaths from cancer each year. It plays a particularly relevant role in pancreatic ductal adenocarcinoma (PDA), where mutation of the KRAS gene is the cardinal genomic event in the vast majority of cases. The classical approach to developing a KRas drug, by outcompeting GTP in the active site, has failed, likely due to the high affinity of mutant KRas for GTP combined with mM GTP concentrations in the cell. Thus, new ideas, novel approaches and synergistic collaborations from lab bench to clinic are required to imagine the means by which we address KRAS mutant cancers therapeutically. The goal of this proposal is to discover, and eventually exploit genetic dependencies unique to KRAS mutant cancer cells. This goal builds on recently developed genetically defined mouse models of PDA, and cancer cell lines derived from them.
Our specific aims utilize strategically coupled steps, integrating an innovative use of murine shRNA libraries in cell lines from genetically engineered mice followed by validation in both human cell lines and in mouse models. Significantly, we anticipate the results will provide key mechanistic insights into KRas processing and signaling, and provide new targets molecules that mutant KRas requires for its oncogenic program.

Public Health Relevance

KRas plays a key role in the development and progression of pancreatic cancer, meets all criteria as the central driver of the disease, but is not druggable by current medicinal chemistry techniques. Thus, this R21 looks to discover and describe genes that are required specifically for KRas (but not other driver oncogenes) to maintain pancreatic cancer growth and survival.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA176561-01A1
Application #
8638428
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Mietz, Judy
Project Start
2014-01-01
Project End
2015-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
1
Fiscal Year
2014
Total Cost
$159,818
Indirect Cost
$46,892
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Hoadley, Katherine A; Yau, Christina; Wolf, Denise M et al. (2014) Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin. Cell 158:929-44